Hepatitis C virus (HCV) infection in humans is remarkably efficient in the establishment of persistent infection by evading host immune surveillance. HCV persistent infection is a major risk factor for the development of hepatocellular carcinoma and autoimmune disease. The high incidence of persistent infection with HCV suggests that this virus has evolved one or more mechanisms to evade and possibly suppress the host immune response. Indeed, HCV core protein, one of HCV viral proteins, has been reported to contain the immunomodulatory function. Human hepatocyte cell line expressing HCV core protein has been reported to upregulate HLA-E, ligand of NK inhibitory receptor, possibly leading to NK dysfunction. However, the mechanism of HCV core-mediated NK cell dysregulation in vivo is yet to be defined. To dissect the molecular mechanism of immune modulation by HCV core, we have developed a murine model of Core-Tg mice by directing the expression of HCV core protein in hepatocytes. In our prior studies, we demonstrated that anti-viral CD8+ T cell function was impaired in Core-Tg mice following Ad-LacZ infection. In addition, the in vivo depletion of NK cells recovered impaired CD8+ T cell function in core-Tg mice. Based on these findings, we hypothesize that HCV core-expressing hepatocytes induce NK inhibitory function to impair antiviral CD8+ T cell responses via NK-mediated alteration of DC activation. In order to test this hypothesis and further investigate the mechanism of NK-mediated inhibition of antiviral CD8+ T cell responses, we will first determine the kinetics of NK cell recruitment and their differentiation in the liver of Core- Tg mice. Second, we will characterize the signaling event involved in the inhibitory NK function in Core-Tg mice. Lastly, we will explore the mechanism for impaired CD8+ T cell responses by NK-DC crosstalk in Core-Tg mice. PUBLIC HEALTH RELEVANCE This project will identify the role of host NK cells in regulating anti-viral activity of CD8 T cells that is critical for clearing viral infection. It focuses on suppression of CD8 T cell responses by HCV viral product, core protein in the liver environment. In addition, our studies will elucidate a potential mechanism for HCV-mediated suppression of CD8 T cell responses. HCV infection is a major problem for human health worldwide and is remarkably efficient in establishing persistent infection. It is believed that the high rate of HCV persistent infection is possibly due to the impaired CD8 T cell responses. Thus, understanding the mechanism of HCV-mediated suppression of CD8 T cell responses will lead to better HCV treatment and vaccines. 1